Topics Organomet Chem (2004) 6: 123–152

DOI 10.1007/b11772

Asymmetric Processes Catalyzed by Chiral (Salen)Metal

Complexes
Jay F. Larrow* · Eric N. Jacobsen
*Amgen, Small Molecule Process Development, One Kendall Square, Cambridge, MA 02139,
USA
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cam-
bridge, MA 02138, USA
E-mail: [Link]@[Link], jacobsen@[Link]

Abstract A wide variety of highly selective asymmetric reactions catalyzed by chiral

(salen)metal complexes have been disclosed over the past decade. Salen ligands are among the
most synthetically accessible frameworks for asymmetric catalysts, and their structures are
readily tuned both sterically and electronically. However, one particular chiral salen ligand (1)
has been demonstrated to be highly effective for a wide variety of useful asymmetric transfor-
mations catalyzed by different metals. The simplicity of this ligand, the high enantioselectiv-
ities and broad substrate generality often observed, and the synthetic utility of the catalytic
transformations have inspired substantial effort directed toward the commercial development
of asymmetric salen chemistry. This chapter surveys the resulting progress.

Keywords (Salen)metal complexes · Asymmetric catalysis · Epoxides · Nucleophiles · Kinetic

resolution

1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
2 Salen Ligand Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . 124
3 Epoxidation Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . 127
4 Epoxide Ring Opening Reactions . . . . . . . . . . . . . . . . . . . . 131
4.1 Hydrolytic Kinetic Resolution of Terminal Epoxides . . . . . . . . . 131
4.2 Other Nucleophilic Epoxide Opening Reactions . . . . . . . . . . . . 135
5 Carbonyl Addition Processes . . . . . . . . . . . . . . . . . . . . . . 141
6 Cycloaddition Processes . . . . . . . . . . . . . . . . . . . . . . . . . 145
6.1 Hetero-Diels-Alder Reaction . . . . . . . . . . . . . . . . . . . . . . . 145
6.2 Diels-Alder Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
6.3 Cyclopropanation Reaction . . . . . . . . . . . . . . . . . . . . . . . . 147
7 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148

© Springer-Verlag Berlin Heidelberg 2004

124 J. F. Larrow · E. N. Jacobsen

1
Introduction
The development of practical catalytic asymmetric processes for both laborato-
ry and industrial scale applications has been enabled greatly by the discovery of
a small number of ligands that exhibit high selectivity for a wide range of sub-
strates and over a broad spectrum of reactions [1]. This group of special ligands
includes BINAP and BINOL, tartaric acid derivatives, bis(oxazoline) and pybox
ligands, derivatives of the cinchona alkaloids, and the Duphos bis(phosphine)
ligands [2] (Fig. 1). Another member of this group of privileged ligands that has
emerged over the past several years is salen ligand 1. Metal complexes of ligand
1 have been successfully applied to a broad range of industrially important
asymmetric reactions. A survey of catalytic asymmetric reactions utilizing these
and related complexes and an evaluation of their utility within the pharmaceu-
tical and fine chemical industries is the focus of this review [3].

Fig. 1 Families of privileged ligands in asymmetric catalysis which show high product selec-
tivity and substrate generality for a number of different reactions

2
Salen Ligand Synthesis
Salen ligands are prepared by the condensation of two equivalents of a salicyla-
ldehyde derivative with a 1,2-diamine, and the simplest, achiral version (bold
structure in Fig. 1) is prepared from salicylaldehyde and ethylenediamine, ab-
breviations of which combine to give this ligand class its name. Chiral versions
of this tetradentate bis(imine) ligand are accessed simply by using chiral 1,2-di-
amines, although ligands derived from other diamines (1,3-, 1,4-, etc.) are often
Asymmetric Processes Catalyzed by Chiral (Salen)Metal Complexes 125

included in this class. Chiral salen ligands have several attractive features that
constitute the basis for their utility in asymmetric reactions. The salicylaldehyde
and diamine components are synthetically accessible and their condensation to
generate the salen ligand generally proceeds in nearly quantitative yield. Metal
complexes of salen ligands are readily prepared from a variety of first row and
second row transition metal salts as well as main group metals. Once the appro-
priate metal for the desired reactivity has been identified, the modularity of syn-
thesis of salen ligands allows for the systematic tuning of catalyst steric and elec-
tronic properties by modification of the metal counterion, the chiral diamine or
the salicylaldehyde components [4]. Although a large number of ligand struc-
tures are thus accessible, it is striking that salen ligand 1 has often been found to
be the optimum ligand for a broad range of reactions catalyzed by several differ-
ent metals (Fig. 2).

Fig. 2 Metal complexes of salen ligand 1 utilized in catalytic asymmetric processes

Salen ligand 1 was first identified in the context of Mn-catalyzed asymmetric

epoxidation of unfunctionalized olefins [5]. Hundreds of salen ligand variations
were investigated for this process, and several reviews are available for a discus-
sion of the results [6]. Figure 3 shows many of the different permutations inves-
tigated, including ligands derived from chiral 1,2-, 1,3-, and 1,4-diamines, chiral
tertiary1,2-diamines, chiral salicylaldehydes, and hydroxyacetophenones. Lig-
and 1 was selected because it showed the best balance between high selectivity
for a broad range of substrates and accessibility from inexpensive raw materials.
The key elements of the ligand are the bulky tert-butyl groups at the 3,3¢- and
5,5¢-positions. These groups are proposed to enforce approach of the substrate
over the chiral diamine portion of the ligand where the trans-diaxial a-protons
provide remarkably effective stereochemical communication.
The industrial synthesis of ligand 1 utilizes very inexpensive raw materials
(Scheme 1) [7], and the ligand is now available commercially in both laboratory
and bulk quantities. A cis/trans mixture of the diamine is a by-product of the
conversion of adiponitrile to 1,6-hexanediamine for the Nylon industry, and is
readily resolved to enantiomeric and diastereomeric purity with tartaric acid
126 J. F. Larrow · E. N. Jacobsen

Fig. 3 Different structural variations of the salen ligand framework investigated for Mn-catalyzed asymmetric epox-
idation (AE)

[7, 8]. Due to the use of unnatural (-)-tartaric acid to isolate the (S,S)-diamine,
(S,S)-1 is slightly more expensive than (R,R)-1. The salicylaldehyde component
is prepared by formylation of 2,4-di-tert-butylphenol, which in turn is pro-
duced inexpensively on large scale by the double alkylation of phenol with iso-
butene.
Asymmetric Processes Catalyzed by Chiral (Salen)Metal Complexes 127

Scheme 1 Commercial synthesis of salen ligand 1

3
Epoxidation Reactions
The first example of enantioselective epoxidation of unfunctionalized olefins
catalyzed by chiral (salen)Mn(III) complexes was reported in 1990 [9], and this
remains an active area of study 12 years later. One of the more practical versions
of this asymmetric process utilizes Mn(III) complex 2 as the catalyst and aque-
ous bleach as the stoichiometric oxidant [5, 10]. Several subsequent variations
of ligand structure, metal center, and terminal oxidant have been developed, but
none have surpassed the utility and practicality of the process depicted in
Scheme 2. The epoxidation process generally requires an unsaturated conjugat-

Scheme 2 General conditions for asymmetric epoxidation (AE) of conjugated olefins cata-
lyzed by Mn complex 2
128 J. F. Larrow · E. N. Jacobsen

ing group such as an arene, alkene, or alkyne for acceptable reactivity. High
enantioselectivities are typically observed with most cis-1,2-disubstituted, as
well as certain tri- and tetrasubstituted olefins [11], while low-temperature, ho-
mogeneous conditions have been developed to access terminal epoxides in up to
86% ee [12]. trans Olefins yield epoxides in low enantiomeric excess, but condi-
tions have been developed that favor the production of high ee trans epoxides
from cis olefins [13]. The use of amine N-oxide additives such as 4-phenylpyri-
dine N-oxide (4-PPNO) can have a profound impact on the ratios of enantiomers
and cis/trans epoxides produced, and serve to improve the efficiency of the cat-
alyst [14]. These additives have been demonstrated to act as axial ligands that
bind to the Mn center trans to the oxo ligand [15].
Diastereomeric epoxide isomers (enantiomers in the case of terminal epox-
ides) are often obtained as primary products from isomerically pure cis-olefins.
This constitutes strong evidence for a mechanism of oxygen transfer from the
metal center to the olefin involving non-concerted formation of the C-O bonds.
Several plausible intermediates have been proposed to lie along this reaction path-
way, but at this stage there is mounting support, based on both experimental and
theoretical studies, for a radical pathway such as the one depicted in Fig. 4 [16].
The synthetic utility of the chiral (salen)Mn-catalyzed epoxidation reaction
has been demonstrated through several important examples. The asymmetric
epoxidation of cis-cinnamates was the key transformation in the practical syn-
thesis of the phenylisoserine side chain of Taxol [17] and in a route to the calci-
um channel antagonist Diltiazem (Scheme 3) [18]. Due to the problem of
cis/trans partitioning noted above, the asymmetric epoxidation process is most

Fig. 4 Stepwise mechanism of oxygen transfer from Mn to olefin leads to diastereomeric mix-
tures of epoxides
Asymmetric Processes Catalyzed by Chiral (Salen)Metal Complexes 129

Scheme 3 AE of cinnamates

Scheme 4 AE of chromenes
130 J. F. Larrow · E. N. Jacobsen

practical for the epoxidation of cyclic olefins where rotation is not possible.
Chromenes represent the best substrates for the AE reaction in terms of enanti-
oselectivity, and there are several pharmaceutically important derivatives of the
epoxides which have been accessed via this chemistry, including the anti-hyper-
tensive agents cromakalim, EMD-52,692, and BRL55834 (Scheme 4) [19].
The asymmetric epoxidation of indene has also been extensively studied be-
cause the epoxide can be transformed into cis-1-aminoindan-2-ol [20], an effec-
tive chiral ligand and an important portion of the HIV protease inhibitor Crix-
ivan [21]. In the optimized process for the epoxidation of indene [22], only
0.6 mol% catalyst was required using 3 mol% of additive, and the productivity
of the reaction was improved by using 10–14% NaOCl solution. For the scale-up
of this epoxidation, it was found that efficient mixing of the biphasic reaction
mixture was critical. Thus, the reaction reaches completion in less than 15 min-
utes if a blender is used. The epoxide is isolated in 84–86% ee by simple distilla-
tion, and is then converted to the cis-amino alcohol by a Ritter reaction followed
by hydrolysis. The enantiomeric excess of the product as well as the chemical pu-
rity are then upgraded by a recrystallization as the (+)-tartaric acid salt
(Scheme 5). An alternative route from indene oxide to aminoindanol involves
opening of the epoxide with ammonia followed by inversion at the 2-carbon via
an oxazoline intermediate [23]. This process has the advantage of using the less-
expensive (R,R)-2 as the catalyst, although the overall route involves more steps.

Scheme 5 AE of indene and conversion to cis-1-aminoindan-2-ol

In contrast to the substrate scope with (salen)Mn-catalyzed asymmetric

epoxidations, (salen)Cr complexes provide high selectivity in the epoxidation of
conjugated trans olefins [24]. Due to its enhanced stability, the Cr(V)-oxo spe-
cies can be isolated and used stoichiometrically, or the corresponding
(salen)Cr(III) complexes can be used catalytically with a stoichiometric oxidant
such as iodosylbenzene. Although the (salen)Cr(V)-oxo complex derived from
1 epoxidizes trans-b-methylstyrene with good enantioselectivity (71% ee vs
24% ee with Mn complex 2), electron-withdrawing substituents on the ligand
provide optimal results [25]. The Mn and Cr systems are fairly complementary
in terms of substrate scope, but the practicality of the (salen)Cr process is limit-
ed by slow reaction rates, low yields, and the necessity of iodosylarenes as the
Asymmetric Processes Catalyzed by Chiral (Salen)Metal Complexes 131

stoichiometric oxidant. In addition to his large volume of work on (salen)Mn-

catalyzed asymmetric epoxidation, Katsuki has pioneered the development of
photoactivated (salen)Ru complexes which catalyze the stereospecific AE of con-
jugated olefins [26]. Other asymmetric oxidation reactions have also been cata-
lyzed by (salen)metal complexes including C-H oxidation [27], sulfide oxidation
[28], sulfimidation [29] and the Baeyer-Villiger reaction [30], but these process-
es have marginal potential for broad industrial application due to substrate and
selectivity limitations.
In summary, the importance of the (salen)Mn-catalyzed asymmetric epoxi-
dation reaction lies in the fact that it was the first process to provide practical ac-
cess to enantiomerically enriched epoxides without the necessity of precoordi-
nation of the substrate via a directing functional group (cf. Ti-tartrate-catalyzed
asymmetric epoxidation of allylic alcohols [31]). Chiral epoxides are versatile
building blocks for asymmetric synthesis due to their regio- and stereochemi-
cally predictable reactivity with a broad range of nucleophiles [32]. Thus, de-
spite practical advantages offered by (salen)metal-catalyzed epoxidation proc-
esses, a substrate scope of conjugated olefins represents a significant limitation.
Clearly, access to simple terminal epoxides is precluded, yet these are among the
most important secondary building blocks of the modern chemical industry.
Since worldwide efforts to develop practical asymmetric epoxidation processes
for a-olefins have been unsuccessful to date [33], an alternative approach has
been developed for access to these important chiral building blocks.

4
Epoxide Ring Opening Reactions
4.1
Hydrolytic Kinetic Resolution of Terminal Epoxides

The substrate limitations of the (salen)Mn-catalyzed asymmetric epoxidation

were successfully overcome with the discovery of the kinetic resolution of ra-
cemic terminal epoxides with water catalyzed by chiral (salen)Co(III) complexes
to produce highly enantioenriched epoxides and 1,2-diols (Scheme 6). The hy-
drolytic kinetic resolution (HKR) process was discovered in 1997 [34], and was
quickly industrialized to provide commercial access to several important chiral
building blocks such as propylene oxide, propylene glycol, epichlorohydrin, 3-
chloro-1,2-propanediol, and methyl glycidate in high enantiomeric excess at
large scale (>100 kg batches). Several of these chiral intermediates have already
been incorporated into processes for synthesizing pharmaceutical agents.
Despite the fact that the HKR is a kinetic resolution and has a 50% maximum
theoretical yield, it possesses a set of characteristics that render it nearly ideal as
an industrial process [35]. First, most simple terminal epoxides are readily ac-
cessible in racemic form at very low cost, and nearly all monosubstituted epox-
ides examined to date have proven to be useful substrates for the HKR (nearly
100 substrates evaluated). As in any kinetic resolution, high enantiomeric excess
of recovered epoxide is attainable as long as the reaction is carried out to high
enough conversion. As a result of the high selectivities obtained in the HKR, re-
132 J. F. Larrow · E. N. Jacobsen

Scheme 6 Hydrolytic kinetic resolution (HKR) of racemic epoxides catalyzed by complex 3b

solved epoxide can usually be recovered in >99% ee in close to the theoretical

yield (40–45%) [36] (Fig. 5). Alternatively, high ee 1,2-diol products can also be
obtained in a practical manner by simply carrying the resolution to slightly low-
er conversion using 0.45 equivalents of water. HKR reactions are typically car-
ried out in the absence of solvent, and the resolved epoxide and diol product are
often easily separated by distillation or extraction. Catalyst 3a is available at any
scale at low cost and is used at low loading levels (0.2–2.0 mol%). Furthermore,
the catalyst can be recovered from HKR reactions of most epoxides and recycled
without loss of activity or selectivity. The use of water as a nucleophile has tre-
mendous practical advantages, as it is inexpensive, safe, easily handled, and of
low molecular weight. The rate of water addition can also be used to modulate
the rate of the reaction in order to help control the heat output from the reaction.
Together, these factors combine to make the HKR process one of the most prac-
tical asymmetric transformations discovered to date.
Kinetic studies carried out on the HKR have allowed formulation of a com-
plete rate expression for this reaction [37]. The most salient feature of the HKR
as well as of other (salen)metal-catalyzed epoxide ring-opening reactions is the
second-order dependence on catalyst concentration. This is consistent with a
dual activation mechanism wherein epoxide is associated to one molecule of cat-
alyst with simultaneous delivery of the hydroxide nucleophile by a second cata-
lyst molecule. This cooperative, bimetallic mechanism also accounts for signifi-
cant non-linear effects observed with this system [38]. Changes in catalyst con-
centration thus have an exponential impact on the rate of the reaction. In prac-
tice, this places a severe limitation on how low a catalyst loading can be em-
ployed, especially with slow-reacting epoxides.
The loss of active catalyst via reduction (3b to 3a) is often observed in HKR
reactions, particularly toward the final stages of the resolution process. Because
of the second order dependence on catalyst concentration, this can make it very
difficult to reach high enantiomeric excess (>98% ee) with slow-reacting sub-
strates. Typically, this difficulty is overcome by the addition of excess water or by
the use of higher catalyst loadings. However, the use of stronger Brønsted acids
Asymmetric Processes Catalyzed by Chiral (Salen)Metal Complexes 133

Fig. 5 Representative epoxides successful in the hydrolytic kinetic resolution (HKR). Isolated yields reflect the amount of recov-
ered epoxide in >99% ee as a percentage of the amount of racemate input

to activate the catalyst has been developed as an alternative to overcome this

problem. The choice of the acid is important because if the conjugate base is too
nucleophilic, it will open the epoxide and the benefit will be lost. Electron defi-
cient benzoic acid derivatives or sulfonic acids (e.g., 4-nitrobenzoic acid or (+)-
camphorsulfonic acid) have been found to provide the optimum catalysts for
134 J. F. Larrow · E. N. Jacobsen

slow-reacting substrates. Although the reactions are often kinetically slower

with these catalysts, the reactions typically reach completion in less time due to
the minimization of the catalyst reduction pathway.
In order to overcome the rate limitations on the HKR reaction imposed by the
second-order dependence on catalyst concentration, attempts have been made
to increase the reactivity of the catalyst by linking multiple reactive metal cent-
ers together. The practicality of such a strategy is clearly tied to the synthetic ac-
cessibility of the linked catalysts relative to the inexpensive monomeric analog 3
[39, 40]. A successful outcome was achieved by preparing C2-symmetric
(salen)Co derivatives linked together by flexible tethers at the 5,5¢-positions of
the salicylaldehyde units. Not only are the requisite ligands readily synthesized,
but the derived cyclic oligomeric (salen)Co complexes display remarkably en-
hanced reactivity relative to the cobalt(III) complexes of ligand 1 [41] (Fig. 6).
The first generation oligomeric catalyst (6a) utilized the a,a¢-dichloropimelate
linker as a mixture of stereoisomers for optimal electronic tuning of the metal
center, but it was later found that the simple pimelate linker could be utilized
with better results by varying the sulfonate counterion of the metal (6b,c) [42].
This change greatly simplified the synthesis of the oligomeric ligand to the ex-
tent that the commercial synthesis of the oligo(salen) catalyst is projected to cost
only 2–4 times the cost of the monomeric catalyst. Also, due to the electron-rich
nature of the oligo(salen) ligand, catalyst reduction is nearly eliminated as a cat-
alyst decomposition pathway.
These novel oligomeric (salen)Co(III) complexes are more reactive than the
monomeric catalyst by orders of magnitude. Not only can catalyst loadings be
dramatically reduced with these complexes, but the scope of reactivity is also

Fig. 6 Structures of highly reactive oligomeric salen complexes

Asymmetric Processes Catalyzed by Chiral (Salen)Metal Complexes 135

widened to include disubstituted epoxides (e.g., cyclohexene oxide) as sub-

strates and primary alcohols as nucleophiles (see next section). The practical
significance of the difference in reactivity between the oligomeric salen catalysts
and the monomeric complexes is best realized by an example. In the HKR of ep-
ichlorohydrin, an optimized catalyst loading of 0.5 mol% (relative to racemate)
requires 1.8 kg of catalyst 3b per 50 kg racemate, or 3.6 wt%. However, the oligo-
meric catalyst currently attains the same reactivity at only 0.005 mol%, which
corresponds to just 50 g of catalyst 6b per 50 kg of racemate (0.1 wt%). At these
levels, the cost contribution of the catalyst to the end product becomes virtually
negligible, and product isolation is greatly facilitated.
In summary, within a remarkably short period from its initial discovery, the
HKR reaction has been applied to the cost-effective industrial synthesis of sev-
eral chiral building blocks. The reaction provides one-step access to enantiopure
terminal epoxides that have not been practically accessible in the past. Many 1,2-
diols are also accessible in high enantiomeric purity utilizing this technology. As
the incorporation of these building blocks in pharmaceutical, agricultural, and
fine chemical applications increases, it is anticipated that the HKR technology
will be transformed from batch operation at present to a continuous mode of
production utilizing a fixed-bed or similar reactor system. Efforts to immobilize
both the monomeric and oligomeric salen catalysts for these applications are
currently underway.

4.2
Other Nucleophilic Epoxide Opening Reactions

The first asymmetric epoxide ring opening (ARO) reaction found to be cata-
lyzed by (salen)metal complexes was the desymmetrization of meso epoxides
with TMSN3 [43], discovered two years prior to the HKR. Meso epoxides under-
go desymmetrization catalyzed by (salen 1)Cr(III) complexes, with good-to-ex-
cellent enantioselectivity for epoxides derived from cyclic olefins, but lower se-
lectivity with acyclic meso epoxides. Best results were obtained with 5-mem-
bered ring substrates (entries 2, 4–5, 7), with lower but still useful ees observed
with cyclohexene oxide (entry 1). Larger ring epoxides performed poorly (en-
try 3), with cyclooctene oxide being completely unreactive (Table 1). The ARO
reaction was extended to the kinetic resolution of racemic terminal epoxides to
provide 1-azido-2-trimethylsiloxyalkane derivatives in high enantiomeric ex-
cess (Table 1, entries 9–18) [44] and of 2,2-disubstituted epoxides where the un-
reacted epoxides could be isolated in high ee [45]. Epoxide ring-opening with
TMSN3 has also been demonstrated to show a high degree of catalyst control in
the regioselective opening of enantiopure dissymmetrically substituted epox-
ides [46].
The ARO/KR reaction is usually run in the absence of solvent, and the prod-
uct can often be recovered in nearly quantitative yield by vacuum distillation.
The catalyst residue (4b) is recyclable, and as many as ten cycles have been dem-
onstrated. In this respect, the ARO reaction is very industrially practical since
two reactants combine to form one product with no waste using a highly selec-
tive, recyclable catalyst. However, commercialization of this technology has not
136 J. F. Larrow · E. N. Jacobsen

Table 1 ARO and KR of epoxides via ring opening with TMSN3

advanced due to the high capital costs inherent in the handling of azides on large
scale.
The primary synthetic utility of the ARO technology is in the preparation of
1,2-amino alcohols in which the oxygen and nitrogen groups are differentially
protected to facilitate further elaboration. Chiral amino alcohols have a rich his-
tory as asymmetric ligands and are a prominent pharmacophore in several
classes of drugs [47]. Both cis and trans amino alcohol products are accessible in
enantiopure form via the ARO of meso epoxides [48]. Several pharmaceutically
active compounds have been synthesized in the laboratory utilizing this technol-
ogy as the key asymmetric transformation (Fig. 7). The ARO desymmetrization
reaction was the key transformation in the synthesis of carbocyclic nucleoside
Asymmetric Processes Catalyzed by Chiral (Salen)Metal Complexes 137

Fig. 7 Biologically active compounds synthesized utilizing ARO or KR as the key asymmetric
transformation

analogues such as Carbovir useful in the treatment of viral infections [49]. Other
applications include key intermediates in the synthesis of prostaglandins [50];
allosamizoline, a component of the allosamidin family of chitinase inhibitors
[51]; Balanol, a natural product inhibitor of protein kinase C [52]; and the 1,2-
aziridinomitosene ring system of the mitomycin antitumor antibiotics [53]. The
kinetic resolution application was utilized in the synthesis of the b-blocker (S)-
propranolol and the antiviral agent (R)-PMPA [44], as well as the natural prod-
uct taurospongin A [54]. Epichlorohydrin was also found to undergo dynamic
kinetic resolution, yielding the product (S)-3-azido-1-chloro-2-trimethylsiloxy-
propane in 97% ee and 76% yield based upon racemic epoxide. This product was
utilized in the synthesis of the novel aryl oxazolidinone antibiotic U-100592
[55].
The ARO displays similar kinetic behavior to the HKR in that it is subject to
a second-order dependence on catalyst concentration; a similar bimetallic
mechanism involving simultaneous activation of nucleophile and electrophile
by distinct catalyst molecules has been postulated for both reactions [56, 57].
Benzylic thiol nucleophiles work best with (salen)Cr complexes, but moderate
levels of enantioselectivity limit the utility of this methodology [58]. Halides
138 J. F. Larrow · E. N. Jacobsen

have shown excellent reactivity as nucleophiles with both catalyst systems, but
enantioselectivities are generally low. Recently, complex 4a has been reported to
be a competent promoter of the enantioselective opening of epoxides with fluo-
ride, but the efficiency of catalysis is poor and the mechanism is unclear [59].
The ARO of meso epoxides with benzoic acid catalyzed by (salen)Co(III) com-
plexes displayed good-to-excellent levels of enantioselectivity, and the highest
ees were obtained with aromatic substituted epoxides such as cis-stilbene oxide
[60]. Although the kinetic resolution of racemic terminal epoxides with carbox-
ylic acid derivatives was not preparatively useful, catalytic regioselective open-
ing of resolved epoxides can be accomplished with most carboxylic acids. This
strategy has been effectively utilized to prepare glycidyl butyrate by opening re-
solved epichlorohydrin with butyric acid followed by ring closure of the chloro-
hydrin to the epoxide (Scheme 7).

Scheme 7 Synthesis of glycidyl butyrate by regioselective ring opening of resolved epichloro-

hydrin with butyric acid

In another application with industrial potential, phenols were found to be ef-

fective nucleophiles for the kinetic resolution of terminal epoxides utilizing the
Co(II) complex 3a as precatalyst (Scheme 8) [61]. Initially, perfluoro-tert-buta-
nol was required as the catalyst activator for good reactivity, but it has since
been demonstrated that electron deficient phenols and 2,6-lutidinium p-tolue-
nesulfonate are more practical catalyst activators [62]. Phenols are highly use-
ful nucleophiles because the a-aryloxy alcohol system is a prominent pharma-
cophore [47]. The dynamic kinetic resolution of epibromohydrin with phenols
was utilized to prepare aryl glycidyl ethers in >99% ee and 74–77% yield based
on racemic epoxide [61, 63]. Aryl glycidyl ethers have been used for the manu-
facture of several b-blockers marketed today including (S)-propranolol (see
Fig. 7) [47].
The ring opening of resolved propylene oxide with 2,3-difluoro-6-nitrophe-
nol was also used in the one-step preparation of a key intermediate in the syn-
thesis of the quinolone antibiotic Levofloxacin [64]. However, the regioselectiv-

Scheme 8 Kinetic resolution (KR) of racemic epoxides with phenols

Asymmetric Processes Catalyzed by Chiral (Salen)Metal Complexes 139

ity of opening is uncharacteristically low at 25–30:1, and the regioisomeric prod-

ucts are prone to equilibrate via a Smiles rearrangement. In order to prevent the
erosion in regioisomeric purity, a method of silyl transfer from phenol to prod-
uct was utilized to halt this rearrangement (Scheme 9) [65].

Scheme 9 Potential industrial routes to the key intermediate in the synthesis of the quinolone
antibiotic levofloxacin

As with the HKR reaction, the ring opening of epoxides with these other nu-
cleophiles has been rendered significantly more practical from an industrial
perspective by the development of the oligomeric (salen)Co catalysts. These cat-
alysts again display enhanced reactivity and selectivity with these nucleophiles
relative to the monomeric catalysts (Table 2). This is even more important with
nucleophiles other than water because higher loadings of the monomeric and ol-
igomeric catalysts are generally required for these reactions. In this context, the
synthetic accessibility of the oligo(salen) catalysts becomes the paramount issue
because the cost contribution of the catalyst to the product is no longer negligi-
ble as it is in the HKR example described in the previous section. In addition, the
range of useful nucleophiles has been expanded to include primary alcohols (en-
tries 4–5), which are effectively unreactive with the monomeric catalysts [66].
Oligo(salen) complexes of metals other than Co(III) have yet to be evaluated, but
enhanced performance and an expansion of the pool of useful reactions can be
reasonably anticipated.
In summary, chiral (salen)Co(III) and Cr(III) complexes have been found to
catalyze the asymmetric ring opening of meso and racemic terminal epoxides
with a high degree of selectivity using a variety of synthetically useful nucle-
140 J. F. Larrow · E. N. Jacobsen

Table 2 Comparison of monomeric and oligomeric catalysts in KR and ARO of epoxides with
hydroxylic nucleophiles

ophiles. Novel cyclic oligo(salen) catalysts have also shown remarkable en-
hancement in reactivity and selectivity relative to monomeric catalysts, leading
to the prospect of additional reactions catalyzed by these complexes. Interest-
ingly, despite a great deal of effort, cyanide and other carbon nucleophiles were
completely unreactive with these catalysts [67]. However, with an overwhelming
body of evidence supporting a cooperative bimetallic mechanism for nucle-
ophilic epoxide opening reactions by simultaneous activation of the nucleophile
and the epoxide by distinct catalytic centers, the question of whether or not this
mechanism was general for a broader range of nucleophile-electrophile reac-
Asymmetric Processes Catalyzed by Chiral (Salen)Metal Complexes 141

tions catalyzed by (salen)metal complexes became paramount. With this in

mind, the search began for new nucleophile-electrophile reactions catalyzed by
chiral (salen)metal complexes.

5
Carbonyl Addition Processes
Because of its great synthetic significance and the fact that it utilizes a novel nu-
cleophile-electrophile pair, the addition of hydrogen cyanide to imines (the
Strecker reaction) was chosen as an ambitious target for asymmetric catalysis by
chiral (salen)metal complexes. The asymmetric Strecker reaction provides facile
access to optically active a-amino acids, but progress in this area was limited un-
til very recently [68]. In the current study, a series of metal complexes of salen 1
were screened for catalysis of the reaction of N-allyl benzaldimine with trimeth-
ylsilylcyanide. Several (salen)metal complexes were found to catalyze the reac-
tion with varying degrees of conversion and enantioselectivity, and the best re-
sults were observed with the Al complex 5a [69]. The actual reactive reagent in
the reaction was determined to be HCN, which could be conveniently generated
in situ from TMSCN and methanol. In order to suppress the racemic back-
ground reaction, the reactions were performed at -70 °C, and the products were
trifluoroacetylated to prevent racemization. A variety of alkyl and aryl N-allyl
imines were evaluated in the reaction, and substituted aryl imines gave the high-
est levels of enantioselectivity (Scheme 10). Alkyl imines yielded products with
more modest ees. Modification of the nitrogen substituent of the imine or of the
steric or electronic properties of the salen ligand proved unsuccessful in improv-
ing the results with these synthetically useful substrates. However, a novel non-
metal catalyst (7) was identified which provided excellent selectivities with all
types of imine structures [70].

Scheme 10 Asymmetric Strecker reaction

142 J. F. Larrow · E. N. Jacobsen

Among the (salen)metal complexes found to be active for the addition of cy-
anide to imines was the Ti(IV)Cl2 complex of ligand 1. This complex was previ-
ously identified by North and Belokon as an asymmetric catalyst for the addition
of TMSCN to aldehydes [71] and ketones [72]. In a limited screening of salen lig-
and substituents, ligand 1 was found to be optimum for this transformation as
well. Subsequently, the Ti(IV)oxo-dimer (8) and the V(IV)oxo (9) complexes of
ligand 1 were determined to be improved catalysts in terms of reactivity (8) or
selectivity (9) for all substrates investigated (Scheme 11) [73]. Like the
(salen)Al-catalyzed addition of HCN to imines, aromatic aldehydes were the
best substrates, although a greater range of selectivities was observed.

Scheme 11 Asymmetric hydrocyanation of carbonyls

Although incompletely elucidated, the mechanisms by which these three

complexes catalyze these similar reactions appear to be distinct from the seem-
ingly general mechanism of nucleophilic ring-opening of epoxides. The
(salen)Al-catalyzed addition of HCN to imines has been determined to be first-
order in catalyst, which would preclude the possibility of a cooperative bimetal-
lic mechanism of nucleophile and electrophile activation [74]. The (salen)Ti-
and (salen)V-catalyzed additions of TMSCN to carbonyls both display a non-
first-order kinetic dependence on catalyst concentration [73], but this has been
attributed to the formation of dimeric catalyst complexes which show greater re-
activity than the monomeric species.
Another reaction found to be catalyzed by (salen 1)Al complexes is the asym-
metric conjugate addition of hydrazoic acid to a,b-unsaturated imides [75]. Us-
ing a simple protocol, excellent enantioselectivities were observed for several N-
benzoyl imide derivatives (Scheme 12), although cinnamate derivatives suffered
from poor reactivity. The b-azido imide products can be readily converted to b-
amino acids.
In another interesting application of chiral (salen)metal catalysis, Bandini et
al. reported an extension of the Nozaki-Hiyama-Kishi coupling to the addition
Asymmetric Processes Catalyzed by Chiral (Salen)Metal Complexes 143

Scheme 12 Asymmetric conjugate addition of hydrazoic acid

Scheme 13 Asymmetric addition of allylic and propargylic halides to aldehydes

of allylic and propargylic halides with aromatic aldehydes (Scheme 13) [76]. The
use of 1,3-dichloropropene has also been investigated as a route to optically ac-
tive vinyl epoxides [77]. Despite being much less developed than alternative tin-
and silicon-based chemistry [78], this work has the advantage of directly utiliz-
ing allylic and propargylic halides from which the corresponding stannanes and
silanes are typically prepared. At this stage, the practical application of these re-
actions is limited by the moderate-to-low yields due to competing side reactions,
the long reaction times, and the requirement of high catalyst loadings (typically
10 mol% plus excess ligand).
144 J. F. Larrow · E. N. Jacobsen

Scheme 14 Y(III)-catalyzed aldol-Tischenko reaction

Several other salen-catalyzed asymmetric transformations involving C–C

bond formation have been reported recently as well. One report utilizes
(salen)Y(III) complexes to catalyze the first enantioselective catalytic aldol-
Tischenko reaction (Scheme 14) [79]. In this case, high-throughput screening of
potential metal catalysts was conducted utilizing the commercially available
salen 1, then the ligand structure was systematically varied to optimize for enan-
tioselectivity. Chiral (salen)Al complexes were also found to catalyze enantiose-
lective aldol reactions of aldehydes and 5-alkoxyoxazoles (Scheme 15) [80].
These catalysts utilized 2,2¢-diamino-1,1¢-binaphthyl (BINAM) as the diamine
component of the salen ligand, and provided the cis products of aromatic alde-
hydes with exceptionally high yield, diastereoselectivity and enantiomeric ex-
cess. The cis products could be thermodynamically equilibrated to the trans
products (5:95 ratio) by treatment with base, and both diastereomers are readily

Scheme 15 Asymmetric 5-alkoxyoxazole aldol reaction

Asymmetric Processes Catalyzed by Chiral (Salen)Metal Complexes 145

Scheme 16 Asymmetric addition of Et2Zn to aldehydes

converted to b-hydroxy-a-amino acid derivatives. Zinc(II) complexes of salen

ligands bearing secondary Lewis basic groups in the 3,3¢-positions have also
been found to catalyze the asymmetric addition of diethylzinc to aldehydes
(Scheme 16) [81]. Rather than simultaneous activation of both nucleophile and
electrophile by the metal center as in the epoxide ring opening chemistry, this
example provides for electrophile activation by the metal center and nucleophile
activation by the secondary basic groups. The structural features of the salen lig-
and allow this concept to operate without catalyst deactivation by these oppos-
ing reactive sites.
This section has summarized the extension of (salen)metal-catalyzed asym-
metric reactions to include nucleophilic additions to carbonyls. The palette of
reactive metals has been substantially broadened to include such diverse metals
as Al, Ti, V, Y, and Zn. Most of the reactions also involve carbon-carbon bond for-
mation, thereby expanding the pool of synthetically valuable reactions even fur-
ther. The (salen)Al catalyst systems stand out due to the exceptionally high
enantioselectivities observed in several reactions. The synthetic utility and high
selectivity of these reactions will surely drive their application to industrial
processes.

6
Cycloaddition Processes
6.1
Hetero-Diels-Alder Reaction

The search for additional reactions promoted by chiral (salen)metal complexes

also led to the identification of (salen)Cr(III) complexes as competent catalysts
for the asymmetric hetero-Diels-Alder (HDA) reaction of aldehydes with 1-
methoxy-3-(trimethylsilyl)oxy-1,3-butadiene (Danishefsky’s diene) [82]. In this
reaction, salen ligand 1 was found to be the best in a limited screen of salicyli-
dene substituents, but the identity of the counterion to chromium was found to
146 J. F. Larrow · E. N. Jacobsen

Scheme 17 Asymmetric hetero-Diels-Alder reaction

be particularly influential on the selectivity and reactivity of the catalysts. Cata-

lysts possessing non-coordinating anions such as BF4- and PF6- showed greater
reactivity and selectivity relative to the chloride catalyst, but only in the pres-
ence of a desiccant such as powdered molecular sieves. Using 2 mol% of the BF4
complex 4c, several synthetically useful aldehydes were reacted to produce dihy-
dropyranones in 70–93% ee and 65–92% yield (Scheme 17). Control experi-
ments revealed the HDA reaction to be a true cycloaddition process rather than
a Mukaiyama aldol reaction followed by acid-catalyzed cyclization [83]. More
recently, improved catalysts based upon tridentate Schiff base complexes of
Cr(III) (10) have been discovered which dramatically improve the scope and
utility of this important reaction [84].

6.2
Diels-Alder Reaction

Subsequent to the report of the asymmetric hetero-Diels-Alder reaction cata-

lyzed by chiral (salen)Cr(III) complexes, Rawal documented the ability of these
catalysts to provide enantioselection in the highly endo-selective Diels-Alder re-
action between 1-amino-1,3-butadiene derivatives and substituted acroleins
(Scheme 18) [85]. As with the hetero-Diels-Alder reaction, the cationic Cr com-
plexes showed greater reactivity and product enantiomeric excess than the chlo-
ride catalysts, although the use of molecular sieves was not critical for good re-
activity. The cyclohexene products of this reaction were produced in greater
enantiomeric excess than the HDA reaction products (generally >90% ee). The
major limitation of this transformation remained reactivity, as the reactions re-
quired several days to reach completion using 5 mol% of catalyst 4d. This prob-
lem appears to have been overcome with a recently reported breakthrough in
Diels-Alder catalysis wherein cationic (salen)Co(III) complexes display unprec-
Asymmetric Processes Catalyzed by Chiral (Salen)Metal Complexes 147

Scheme 18 Asymmetric Diels-Alder reaction

edented catalytic activity (requiring as little as 0.05 mol% catalyst) [86]. Cata-
lysts (11) possessing trialkylsilyl groups at the 3,3¢-positions showed greater re-
activity and selectivity than Co complex 3c.

6.3
Cyclopropanation Reaction

Although carbene transfer from metal to olefin is mechanistically more similar

to oxene transfer in epoxidation reactions, the cyclopropanation of olefins with
diazoesters is formally a [2+1] cycloaddition and is thus covered in this section.
If there are two unequal substituents on the carbene atom, two diastereomeric
products are possible with monosubstituted olefins. Katsuki has demonstrated
high trans- and enantioselectivity with (salen)Co(III) complexes (12) that have
no substituent at the 3,3¢-positions of the salen ligand [87]. Utilizing second gen-
eration salen ligands bearing axially chiral salicylaldehyde derivatives, Katsuki
has also demonstrated high cis selectivity with Ru(III) (13) [88] and Co(II) (14)
complexes (Scheme 19) [89]. Product yields are generally higher with the Co cat-
alysts, while all three catalysts show exceptional enantioselectivity (>90% ee).
The process to trans cyclopropane products seems especially practical due to the
accessibility of the salen ligand.
At this stage, all three cycloaddition processes remain of academic interest,
but each offers promise of future industrial utility. The utility of the asymmetric
hetero-Diels-Alder reaction primarily results from the synthetic versatility of
the pyranone products due to their high degree of functionalization. The un-
precedented catalytic activity of readily available (salen)Co complexes in the
Diels-Alder reaction offers practical advantages in the asymmetric synthesis of
chiral cyclohexenes. Alternatively, the cyclopropanation processes show excel-
lent selectivities and offer better diastereocontrol relative to traditional Cu- and
Rh-catalyzed systems [90].
148 J. F. Larrow · E. N. Jacobsen

Scheme 19 Highly diastereoselective asymmetric cyclopropanation reaction

7
Conclusion
Over the past decade, chiral (salen)metal complexes have emerged as versatile
catalysts for a broad range of industrially and academically interesting reac-
tions. Since its discovery as an optimum ligand for (salen)Mn-catalyzed asym-
metric epoxidation reactions in 1991 [5], metal complexes of salen ligand 1 have
displayed remarkable effectiveness in a wide variety of catalytic asymmetric re-
actions. Ligand 1 and its metal complexes are available commercially at relative-
ly low cost, and the Mn-catalyzed asymmetric epoxidation and Co-catalyzed hy-
drolytic kinetic resolution processes are currently practiced on industrial scale.
In addition, new discoveries such as the extraordinarily high levels of reactivity
and selectivity observed with the oligomeric (salen)Co complexes in epoxide
ring opening reactions portend a continued bright future for salen ligands in
asymmetric catalysis. As insight is gleaned into the factors controlling reactivity
and stereoselection, rational design of improved ligands becomes likely. Howev-
er, at this stage, salen ligand 1 still defines the standard by which others are eval-
uated.

References
1. For comprehensive coverage of the field of asymmetric catalysis see: Pfaltz A, Jacobsen
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2. For an historical review of asymmetric catalysis which discusses most of these ligand
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3. Due to space limitations, salen ligands derived from chiral salicylaldehydes and/or
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Asymmetric Processes Catalyzed by Chiral (Salen)Metal Complexes 149

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Larichev VS, Moscalenko MA, North M, Orizu C, Tararov VI, Tasinazzo M, Timofeeva
GI, Yashkina LV (1999) J Am Chem Soc 121:3968. (d) For synthetic application, see: Lu
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